Thiuronium compounds



Patented Apr. 3, 1951 THI'URONIUM COMPOUNDS Louis H. Bock, Huntingdon Valley, Pa., Norman H. Leake, Bristol, Tenn., and James'L. Rainey, Abington, Pa., assignors to Rohm & Haas Company, Philadelphia, Pa

ware

N Drawing.

' This invention concerns new thiuronium salts.

It further relates to the process by which they are prepared. V V v More particularly, this invention deals with thiuronium salts having the formula Rphen 1- oA ,.so

blHR

wherein R represents a hydrocarbon group of four to twelve carbon atoms, R is hydrogen or a lower alkyl group such as methyl, ethyl, or butyl, A'is an alkylene group of two to three carbon atoms, 11. is an integer from one to three, and HX represents an equivalent of an acid having the anion X.

'These new thiuronium salts differ from previously known thiuronium compounds both in structure and in usefulness. Although some thiuronium salts have been described having as the S-substituent such group as an alkyl, carbalkoxyalkyl, or alkoxyalkyl group, these do not exhibit the marked bactericidal and fungicidal action which is possessed by the thiuronium salts of this invention. n

The new salts are characterized by high bactericidal and bacteriostatic activity. They are especially effective against Gram-negative organisms. They are water-soluble and surfacea r a Th ack h nt e y b t tewh c is common to some of the other types of bactericide s which have recently become widely used. The compounds of this invention are useful as disinfectants for surgical instruments, dairy equipment, crockery, glassware, food storage bins, food wrappers, food machinery, and the like. They may be applied to textile fabrics and the like to prevent fungal attack. They are effective against fungi on living plants.

The new thiuronium salts are prepared by re acting'a'phnoxya1ky1 jhalide, 'with""athiourea. Temperatures from about 50 C. to 150 C. are generally used. The reaction .is desirably carried out in the presence of an inert organic solvent. Solvents such as alcohols, esters, ethers, nitrocompounds, and hydrocarbons may be used. Acetonitrile and formamide are other solvents which have been found suitable. -The products are usually solids which can be obtained as residues and which can berecrystallized for purificationinmany cases. I v 1.

As a phenyl ether halide, there may be used compounds of the formulav R-phenyl-(OAMX parts of ethyl alcohol. The mixture was stirred a corporation of Dela- Application February 23, 1949, Serial No. 77,994 I 4 Claims. (01. 260564) R is a hydrocarbon group of four to twelve carbon.

Particularly suitable are-secondary and atoms. tertiary alkyl groups, such as secondary ortertiary butyl, amyl, hexyl, heptyl, octyl, decyl, and dodecyl groups. Other types of hydrocarbon groups may be used, such as alicyclic, represented by terpenyl and cyclohexyl; aralkyl, such as benzyl; aryl, such as cresyl or tert.-butylphenyl; unsaturated aliphatic groups such as undecenyl or the like. Other unreactive substituents may be present in the phenyl nucleus, such as alkyl, alkoxy, acyl, or halo. Typical of these are methyl, isopropyl, butyl, methoxy, ethoxy, acetyl, and like groups. A is an alkylene chain of two to three carbon atoms and is ethylene, 1,2-propylene, or trimethylene. X may be chlorine, bromine, or iodine.

Typical starting compounds are tert.-butylphenoxyethyl bromide, tert.-amylphenoxyethoxyethyl bromide, methyl-tert.-butylphenoxyethoxyethoxyethyl bromide, (2-0ctyl) phenoxyethyl chloride, diisobutylphenoxyethoxyethyl chloride, tert.- dodecylphenoxyethyl bromide, terpenylphenoxyethoxyethoxyethyl chloride, undecenylphenoxyethoxyethyl bromide, p,1 ,3,5,7-tetramethyl-- octylphenoxyethoxyethyl bromide, etc.

Thiourea itself or a monoalkyl derivative thereof may be used. The alkyl group is an N-substituent and is desirably of not over four carbon atoms. Presumably the imino-group and the amino-group are tautomeric. y The following examples are illustrative of procedures which are appropriate for the preparation of the new thiuronium salts of this invention.

EXAMPLE 1 There were mixed 98 parts by Weight of p- 1,1,3,3-tetramethylbutylphenoxvethyl bromide, 19

' parts of thiourea, and 125 parts of ethyl alcohol.

The tetramethylbutylphenoxyethyl bromide was prepared by mixing 236 parts by weight of ethylene dibromide, 206 parts of p-1,1,3,3-tetra-' methylbutylphenol, '136 parts of water, and 100' The ethyl alcohol was then re-' and heated under refiux. Thereto over a period of an hour there was added a solution of 44 parts of sodium hydroxide in 60 parts of water. Thereafter heating and stirring were continued for ten hours. An oil layer formed and was separated. 5 The phenol coefficient of the tetramethylbutyl- It was distilled at 158 C.l6l C./0.2 mm. phenoxyethyl thiuronium chloride was 238 against The phenol coeflicient of the above thiuronium E. typhi and 83 against Staph. aureus. 7 salt was determined by the F. D. A. method at 20 Tests made to determine the highest dilutions C. with Eberthella typhi and Staphylococcus at which this compound gave bacteriostatic aureus and found to be 500 and 330 against the 10 (Bs) and bactericidal (Be) actions are sumrespective organisms. marized in Table 11.

Tests were made to determine the highest 'Table II dilutions at which this compound gave bacterio- V static (BS) and bactericidal (Bc) actions. Diluggs,ggagggagggggsgyggagggg tions were made in a trypticase-soy broth. The results are summarized in the following. table Dilutions in which organisms used are related to the dilu-. Organism tions. B5 B0 Table I v DILUTIONS QF S-DIISOBUTYLEHENOXY sa ltauzecs 04,000 16,000 ETHYLTHI-URONIUM BROMIDE 8,307 62, 000 2. 8% 'f" N. catarrhn'lit 1281000 04l0j00, Dilutions Etyphi 4, 4,000 Organism -M gi w l filfl 4@ 2.3 3 15. Bs Be 25 Staphylococcus aureas 256,000 4,000 EXAMPLE 3 z ggf 3' There were mixed 201 parts of p-I,1,3,3-tetra- Netsse iz'a'vdiarrhal 5121000 512} 000 methylbutylpheno:gyethoxyethyl chloride, 90 parts 651-196;! g of thiourea, 300 parts of toluene. The mixture Prot eueoulqarisul 21000 11000 was stirred and heated under reflux (110 C5115? 553 3g C.) for 24 hours. The solvent wasstr'ipped ofi by heating on a steam bath under reduced'pressure. The highest dilution was determined at which ggfiggfiggiggggifi: f n gf f g fi fi this thiuronium salt was bactericidal in hard wa- 06016 d d t r f s i ter against Escheiichia coli. The water had a an e S W orme 5 W tseparated and ail-dried. The matenal correnatural hardness of 315 P. P. M. The time of bnded in Om bsfi n t v eigposure was one to three minutes. A complete. c p O 0 NH 5111 was obtained even at a dilution of 1 to 3,000. 7 A similar test, was, made with sterile whole 40 C QH4 Q H94: mill; at 1% in distilled water. Hereth'e tests sh'qwedfcompktekn t 1 to 1,000m 30 seconds, a Y at to 2. n i i t nd at 1 M1000. await???aiilli iiihi itieifif agamit- 1!! mmute? Tests made to determine highest dilutions for ten mlfi mm bacteriostatic and bactericidal actionsa re pie ty pm, at 37 C. in a phenol coefficient type of sentedin Tablem testwas 1 to 60.0.00. Table III EXAMPLE 2 EEEEQTLVE DILUTIQN-S- .OF .S-DIISOBUTYLPHENQXY, There were mixed 202 parts of l,1', 3 3-tetra- X Q E Q PTEI QB N M BPQ I E f methyl u y phenoxyethyl h o 58 Parts. thiourea, and 400 parts of ethanol. The mix: Dilutiau ture was heated under reflux for-17.5 hours sae sm Y Part oi" the ethanolwasdistil'led OK and the B5 B6: reaction mixture was cooled. 'I'hereupon 2,000 parts, of ethyl, ether was added. Crystals formed, a -9 ,7 were separated, and'drie'd a t. room temperature. 21.17 .1 5. The product, thus, obtained amounted to 1165 g Zi igllgggf parts by h 6.5%. yi l nd or pon ed s'mifizm'stis'nji 6410005.: 32,3000 Qm Q tio to 00 r 641W QtHHGQoznlsc Anct, 4tv

\NHZI Thererwere taken 25: parts of the thiuronium: chloride prepared in Example 3; This. was dis. zz g gg gfi g ig gi gi 103% solved in hot ethyl al'cQholeand-thereto was addedk 16; parts of sodium acetate-in 150. partsof ethyl The tetramethylbutylphenoxyethyl chloride alcohol Sodium chloride was precipitated and was prepared by mixing and-heating together at filtered off. The alcohol was evaporated under 90 Q4000 Steam bath for three and reduced pressureran'di the residuehwas crystallized. half hours 469 parts of beta-chloroethyl p-toluene 7 on cooling The crystals were filtered OE and} sulfionate, 42 3.jpartsofip-tetramethylbutylphenol. T 83 pants: of sodium y m and 2200 parts of dned. They corresponded 111.compos1t1onto.v water. The reactionsmixture was cooled. A crystalline solid was. separated. The mixture. CBH11OOCQH4OCQH4SC -HO0CCH: wasjmade. alkaline with sodium hydroxide and? T extracted with benzene. The benzene layer was separated, dried, and distilled. The product was obtained by distillation at 1'74182 C./ 8 mm. The yield was 465 parts.

NHCHz Phenol coefficients were determined as 77 against E. typhi and 420 against Staph. aureus.

EXAMPLES There were mixed 541 parts of p-tert.-amylphenoxyethoxyethyl chloride, 152 parts of thiourea, and 500 parts of toluene. The mixture was stirred and heated under reflux for 23 hours. The toluene was distilled off under reduced pressure. The product was crystallized from ethanol and ethyl ether. It corresponded in composition to A phenol coefficient of 71 against E. typhz was found. The product had a very mild taste.

The abovepreparation was repeated with an equivalent weight of tert.-butylphenoxyethoxyethyl chloride. The product obtained was identifled as This compound had a phenol coefiicient of 74 against E. typhi and was a relatively innocuous compound as to odor and irritation.

The repetition of the above preparations with tert.-amylphenoxyethoxyethyl bromide and tertbutylphenoxyethoxyethyl bromide leads to the corresponding thiuronium bromides. These are even more favorable as to odor and irritation than the above chlorides.

Repetition of the above preparation with isododecylphenoxyethoxyethyl bromide leads to the compound A particularly useful form of the C12 group is the tetraisopropyl group and the salt obtained as the end-product is of the same empirical formulas as that last-given.

Likewise, di(tert.-butyl)phenoxyethoxyethyl chloride was reacted with thiourea. The product had the structure 03 600 1140 o.H.sc

O NH: 1 03 It gave phenol coefficients of 138 against E. typhz' and 125 against Staph. aureus.

Another variation which has been examined The nitroture H r A It too was highly effective as a bactericidal and fungicidal agent.

There were mixed 401 parts by weight of p-diisobutylphenoxyethoxyethoxyethyl bromide and '76 partsof thiourea in 400 parts of xylene. The

I mixture was heated gently at first andthen under full reflux for eight hours. The product was obtained as a residue by removing the solvent under reduced pressure. The product corresponded in composition to NH p-CaH CsH4(OCzHl) 3S0 -HB1 It has a phenol coefiicient of about 400 against the common test organisms and is very mild and innocuous in the dilute solutions which are effective because of the bactericidal and fungicidal eficiency of this substance.

In testing the compounds of this invention bactericidal efficiency was measured in a number of ways and against various organisms. Phenol coeflicients were determined by the F. D. A. method at 20 C. and represent the ratio of effective dilution of the compound under test to the eilective dilution of phenol.

Tests were also run against pathogenic organisms by a dilution method utilizing trypticase-soy broth. One per cent solutions of the product under test were diluted with broth and several dilutions autoclaved for ten minutes at 10 to 12 lbs. pressure. The dilutions were cooled and inoculated With a 4 mm. loopful of a test organism culture. Incubation was carried out at 37 C. for 24 hours. The highest dilution showing no growth gave the end-point for bacteriostatic action. After an additional 24 hours of incubation at 37 C. subcultures were made by transferring three loopfuls from cultures showing no growth to freshtrypticase-soy broth. The subcultures were incubated 48 hours. The highest dilution showing no growth was taken as the endpoint of bactericidal action.

The compounds of this invention have also been tested by the slide germination method against Macrosporz'um sarcznaeforme and Sclerotz'm'a fructz'cola and found to be inhibitive to germination at dilution ratios from 1' to 10,000 to Typical compounds have been applied to livwherein R represents an alkyl group of four to twelve carbon atoms, R is a member of the'class consisting of hydrogen and the alkyl groups of not over four carbon atoms, A is an alkylene group. of two te three carbon atoms, 22 is anmte;

. ger'from one to three, and is an equivalent an acid havingan anion X.

2. As a new chemical substance, p-1,1,3,3-Vtetv-'- ramethylbutylphenoxyethoxyethyl ghiuronium halide.

3. As a new chemical substance, p:1,1,3,3-tetramethylbutylphenoxyethyl thiumnium bromide.

4. As a new chemical substance, p-1,1,3,3-tetramethylbutylphenoxyethyl thiuronium chloride. 19

UNITED S ATE Number 

1. AS NEW SUBSTANCES, COMPOUNDS OF THE FORMULA 